Intermediates for use in the preparation of vitamin E

ABSTRACT

Intermediate compounds which can be used in the preparation of phytone and Vitamin E, a process for the preparation thereof, and a process for the preparation of phytone and Vitamin E from these intermediate compounds.

The present invention relates to a process for the preparation ofintermediate compounds useful in the preparation of phytone and/orVitamin E.

Vitamin E has been prepared chemically for a long time using manyvarious processes. In general, this vitamin is prepared from anintermediate compound. European Patent 0544588 discloses a process forthe production of Vitamin E through the condensation of apolyunsaturated allyl alcohol derivative. U.S. Pat. No. 3,867,408discloses the preparation of novel ketal compounds which may be used inthe preparation of phytone which in turn is an intermediate in theproduction of Vitamin E.

We have now found a new process for the preparation of certain betaolefinic compounds which can be used to synthesise phytone and in somecases which can be used to synthesise vitamin E directly from thisintermediate.

Accordingly, the present invention provides a process for thepreparation of a compound of general formula (I)

wherein A is a C₁ to C₂₀ hydrocarbon, Y and Z independently represent aC₁ to C₂₀ hydrocarbon which may contain an oxygenated functional group,and B represents OR¹ or NHR¹ where R¹ is hydrogen or a C₁ to C₆hydrocarbon, which process comprises reacting, in the presence of aLewis acid catalyst, a compound of the general formula (II)

wherein Y and Z are as herein before defined with a compound of thegeneral formula (III) or a compound of general formula (IV)

wherein A, B and R are as hereinbefore defined and R is hydrogen or a C₁to C₆ hydrocarbon.

Certain compounds of general formula (I) are novel and as such also formanother aspect of this invention.

The process of the present invention comprises the catalytic reactionbetween a compound of general formula (II) and a compound of generalformula (III) or general formula (IV). With regard to the compound ofgeneral formula (II), Y and Z represent a C₁ to C₂₀ hydrocarbon whichmay contain an oxygenated functional group. The hydrocarbon group may belinear, cyclic, aromatic or aliphatic, substituted or unsubstituted.Where Z is a hydrocarbon, the preferred hydrocarbon is a linearaliphatic hydrocarbon, especially methyl. Compounds of general formula(II) suitable for use in the process of the present invention include6-methyl-6-heptene-2-one; 2-methyl-1-heptene; 2,6,10,14 tetra methylpentadec-1-ene, 6-acetoxy 2,5,7,8-tetramethyl 2-[(4-methyl pent-4-ene)-1yl]chromene and 6-acetoxy 2,5,7,8-tetramethyl 2-[(4-methyl pent-4-ene)-1yl]chromane. The particularly preferred compounds of general formula(II) are 6-methyl-6-heptene-2-one; 6-acetoxy 2,5,7,8-tetramethyl2-[(4-methyl pent-4-ene)-1 yl]chromene and acetoxy 2,5,7,8-tetramethyl2-[(4-methyl pent-4-ene)-1 yl]chromane.

With regard to compounds of general formula (III), A represents a C₁ toC₂₀ hydrocarbon. The hydrocarbon may be linear or cyclic, substituted orunsubstituted and may be saturated or unsaturated. Preferably, A is alinerar aliphataic hydrocarbon, especially mathyl. B represents OR¹ orNR¹ where R¹ is a C₁ to C₆ aliphatic linear or cyclic hydrocarbon or aC₆ aromatic hydrocarbon. Compounds of general formula (III) particularlysuitable for the process of the present invention include 3 methylbutanal; imines of 3-methyl butanal; 3,6-dimethyl octanal; imines of3,6-dimethyl octanal; citral and imines of citral. By imine is meantmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl,phenyl, tosyl and benzyl imines, prepared according to known methods.

With regard to compounds of general formula (IV), A represents a C₁ toC₂₀ hydrocarbon. The hydrocarbon may be linear or cyclic, substituted orunsubstituted and may be saturated or unsaturated and R is a C₁ to C₆aliphatic linear or cyclic hydrocarbon or a C₆ aromatic hydrocarbon.Compounds of general formula (IV) particularly suitable for the processof the present invention include acetals of citral; acetals of 3-methylbutanal; acetals of 3,6-dimethyl octanal, The particularly preferredcompound is 3,6-dimethyl octanal, 3-methyl butanal, and their acetals.By acetals, it is meant methyl, ethyl, isopropyl acetals and glycolprepared according to known methods.

The mole ratio of compound of general formula (II) to compound ofgeneral formula (III or IV) is suitably from 0.2:1 to 5:1, preferablyfrom 0.5:1 to 2:1.

The process of the present invention is carried out in the presence of aLewis acid. Suitable Lewis acids include compounds of the generalformula M(L)n wherein M represents aluminium, iron, magnesium, scandium,ytterbium, zinc, titanium, silicium and bismuth; L represents a halide,CF₃SO₃, (CF₃SO₂)₂N, ClO₄ or a C₁ to C₄ alkyl, and n corresponds to theelectronic valency of M and suitably is from 1 to 4. Alternatively, theLewis acid may be a hydride compounds having the general formula A-Hwherein A represents CF₃SO₃ or (CF₃SO₂)₂N.

In particular, Lewis acids according to the aforementioned definitionssuitable for use in the process of the present invention include themetal chloride, for example the chloride of aluminium, iron, bismuth,zinc, magnesium, titanium, scandium and yttrium, trifluoromethanesulphonates of scandium, ytterbium, iron and aluminium; trifluoromethanesulphonic amide or the corresponding metal salt of scandium, ytterbium,iron and aluminium; and trifluoromethane sulphonic acid. The preferredLewis acid is iron trichloride. The amount of catalyst used in theprocess is suitably from 0.001 to 5 molar equivalents, preferably from0.02 to 2.5 molar equivalents.

The process of the present invention may be carried out in the presenceof a base. Suitable bases may be chosen from aromatic amines, forexample pyridine and 2,6, dimethyl pyridine; or aliphatic amines,especially tertiary amines, for example triethyl amine and di-isopropylethyl amine; or an inorganic carbonate, especially a carbonate of GroupI or Group II of the Periodic Table, for example carbonates of sodium,potassium, calcium and magnesium. The preferred base is pyridine. Theamount of base used in the process may be from 0 to 1 molar equivalent,preferably from 0.1 to 0.5 molar equivalent.

The reaction may be carried out in the presence of an organic solvent.Suitable solvents include chlorinated solvents such as dichloromethane,chloroform or chlorobenzene; aromatic solvents, for example toluen eandxylene; ether such as tetrahydrofuran, diethyl ether and isopropylether; nitrile solvents such as acetonitrile, proponitrile, andbenzonitrile and nitro solvents such as nitromethane and nitroethane.The amount of solvent present in the reaction system is suitably from 0to 100, preferably from 2 to 10 mass equivalents.

The process may be carried out at a temperature from minus 80 to plus150° C., preferably from minus 50 to plus 25° C. and under atmosphericor elevated pressure. Preferably, the reaction is carried out underatmospheric pressure.

The process of the present invention may be carried out for a period oftime from 30 minutes to 24 hours, preferably from 30 minutes to 6 hoursunder the aforementioned reaction conditions in order to facilitatecomplete reaction of compounds of general formula (II) or (III).

Certain compounds of general formula (I) are novel and as such formanother aspect of the present invention. In particular compounds offormula V, VI, VII and VIII are novel compounds.

The compounds of general formula (I), obtained by the process of thepresent invention, are particularly suitable for use as startingmaterials in the synthesis of phytone and/or Vitamin E. Thus, accordingto another aspect of the present invention there is provided a processfor the preparation of phytone and/or Vitamin E, which comprises thehydrogenolysis of the compound of general formula (I).

In a specific embodiment of this synthesis, Vitamin E may be obtainedwhen the starting material is selected from compound (VII) or (VIII),where Y is a hydrocarbon containing a chromane or chromene moiety, ashereinbefore defined and phytone may be obtained when the startingmaterial is selected from compound (V) or (VI), where Y is a linear C₅ketone.

The hydrogenolysis stage of the process may be carried out in thepresence of hydrogen gas and in the presence of a metal or metal salt.Suitable metals and metal salts include Raney nickel (a nickel/aluminiumalloy) optionally in the presence of iron, mangenese, cobalt, copper,zinc or chromium; zinc in the presence of acetic acid; stannouschloride; and molybdenum (III) salts. The reaction may also be carriedout in the pressence of palladium or platinum which may be supported onan suitable inert support such as charcoal. The hydrogenolysis ispreferably carried out in the presence of palladium on an inert supportsuch as on charcoal. The amount of metal or metal salt employed isgenerally from 0.01 to 3 molar equivalents, preferably from 0.05 to 2molar equivalents.

The reaction may be carried out in the presence of a solvent which maybe selected from an organic acid such as acetic acid; ethers; andaromatic hydrocarbons. The preferred solvents are acetic acid andtoluene. The amount of solvent is suitably between 0 and 20 weightequivalents. The reaction may also be carried out in the presence of ainorganic acid, for example HCl or sulphonic acid. The amount ofinorganic acid suitably is from 0 to 1 equivalents, preferably from 0.1to 0.5 equivalents.

The reaction temperature may be from 20° C. to 150° C., preferably from20° C. to 90° C. and under a pressure of 1 to 50 bars, preferably 1 to10 bars.

The present invention will now be illustrated with reference to thefollowing examples:

Examples 1 to 6 are directed to the production of the intermediatecompounds, Examples 7 is directed to the production of a phytoneintermediate and Examples 8 is directed to the production of Vitamin E.

In the following examples Tf represents F₃CSO₂.

EXAMPLE 1

The reaction, as detailed below was carried out in the presence ofdichloromethane solvent using various Lewis acid catalysts and underconditions as indicated in Table 1

Eqimolar quantities of the two reactants were added under an inertatmosphere to the reactor containing the catalyst. The reaction was leftto proceed for two hours before adding aqueous saturated sodium hydrogencarbonate magnesium sulphate, filtered and concentrated. The product wasisolated by chromatography on silica gel or filtrated in crude solutionafter concentration of. The resulting product was extracted with ether,washed with water and dried using the solvent. The results are given inTable 1.

TABLE 1 Temperature of Yield of Catalyst and Amount Reaction (° C.)Product (%) 2.5 eq EtAlCl₂ −30 85 5% Tf₂NH 0 58 5% Al(NTf₂)₃ 0 15 idem+5% pyridine 20 50 5% Yb(NTf₂)₃ 0 5 5% Yb(NTf₂)₃ 20 70 5% Yb(OTf)₃ 20 355% Al(OTf)₃ 20 40 5% AlCl₃ 20 15 5% FeCl₃ 20 74 5% BiCl₃ 20 30 5% ZnCl₂20 5 5% TfOH 20 30 5% TiCl₄ 20 5

EXAMPLE 2

The reaction, as detailed below was carried out in the presence ofdichloromethane solvent at 0° C.

An equimolar mixture of 2,6,10,14 tetra methyl penta dec-1-ene (532 mg)and acetal (302 mg) was added under an inert atmosphere to the reactorcontaining 28 mg (0.049 equivalent) of (F3CSO₂)₂NH catalyst. Thereaction was carried out for 2 hours at 0° C. and then 2 hours at 20° C.prior to the addition of aqueous saturated sodium hydrogen carbonate.The resulting product was extracted with ether, washed with water anddried using magnesium sulphate, filtered and concentrated. The productwas isolated by chromatography on silica gel or filtrated in crudesolution after concentration of the solvent. A yield of 54% was obtainedafter purification.

EXAMPLE 3

The procedure of Example 1 was repeated using the reactants as detailedin the reaction scheme below.

The reaction conditions, catalysts used and the resulting yields aregiven in Table 2 below.

TABLE 2 Temperature of Yield of Catalyst and Amount Reaction (° C.)Product (%) 5% Yb(NTf₂)₃ 20 70 5% Al(NTf₂)₃ 20 60 5% Al(OTf)₃ 20 53 2.5eq EtAlCl₂ −15 5

EXAMPLE 4

The procedure of Example 1 was repeated using the reactants as detailedin the reaction scheme below.

The reaction conditions, catalysts used and the resulting yields aregiven in Table 3 below.

TABLE 3 Temperature of Yield of Catalyst and Amount Reaction (° C.)Product (%) 2.5 eq EtAlCl₂ −30 50 2.5 eq AlCl₃ −30 50 2.5 eq FeCl₃ −3042 2.5 eq BiCl₃ −30 18 2.5 eq ZnCl₂ −30 38 2.5 eq MgCl₂ −30 5 2.5 eqAlCl₃ + 0.5 eq pyridine −30 70 2.5 eq FeCl₃ + 0.5 eq pyridine −30 80 2.5eq BiCl₃ + 0.5 eq pyridine −30 5 2.5 eq ZnCl₂ + 0.5 eq pyridine −30 21

EXAMPLE 5

The reaction, as detailed in the reaction scheme below, was carried outin the presence of dichloromethane solvent at 0° C.

An equimolar mixture of the two reactants was added under an inertatmosphere to the reactor containing 2.5 mole equivalent of dichloroethyl aluminium catalyst (in a solution of 1.8 M dichloromethane). Thereaction was carried out for 2 hours at 0° C. in aqueous saturatedsodium hydrogen carbonate. The resulting product was extracted withether, washed with water and dried using magnesium sulphate, filteredand concentrated. The product was isolated by chromatography on silicagel or filtrated in crude solution after concentration of. The resultingproduct was extracted with ether, washed with water and dried using thesolvent. A yield of 10% was obtained.

EXAMPLE 6

The procedure of Example 1 was repeated using the reactants as detailedin the reaction scheme below.

The reaction conditions, catalysts used and the resulting yields aregiven in Table 4 below.

TABLE 4 Yield of Nature of Temperature Product R Group Catalyst andAmount of Reaction (° C.) (%) methyl 2.5 eq AlCl₃ −30 60 methyl 2.5 eqAlCl₃ + 0.5 eq pyridine −30 70 isopropyl 2.5 eq AlCl₃ + 0.5 eq pyridine−30 40 methyl 2.5 eq FeCl₃ + 0.5 eq pyridine −30 92

EXAMPLE 7

Hydrogenolysis of the product obtained in examples 4, 5 and 6 wascarried out in the presence of a hydrogenolysis catalyst underexperimental conditions as given in Table 5 below and as detailed in thereaction scheme below.

The reactant and the catalyst were placed in an autoclave. The solventwas added. The autoclave was purged with argon prior to sealing.Hydrogen was then introduced into the autoclave to initiate thereaction. At the end of the reaction, the pressure was reduced toatmospheric pressure. The autoclave was then opened. The yield ofproduct is shown in Table 5.

TABLE 5 H₂ Pressure Solvent Catalyst (bar) Conditions Yield of ProductAcetic 7% Pd/5%-C  5  20° C., 30% phytone, 70% acid 6 hours intermediateAcetic 5% Pd/10%-C 50 100° C., 30% phytone, 70% acid 2 hoursintermediate Acetic 30% Pd/10%-C 15  50° C., 30% phytone, 70% acid 5hours intermediate toluene 50% Pd/50% HCl  1  20° C., 80% phytone, 20% 2hours intermediate

EXAMPLE 8

Preparation of Vitamin E starting from 6-methyl 6-hepten 6-2-one,according to the following scheme:

Step (a): Preparation of Alpha-Linallol

24.7 ml of a 1.7 M solution of vinyl magnesium chloride in THF (42mmols) was placed in a flask equipped with two necks, under argon. Thesolution was heated to 35° C., and 3.812 g (30 mmol) of 6-methyl6heptene-2-one was introduced drop by drop to the magnesium compoundover a period of 75 minutes. The mixture was then poured on to a mixtureof 20 g of ice, 24 ml of water and 4 ml of 37% hydrochloric acid. Theresulting organic phase was separated, dried over magnesium sulphate andconcentrated. The yield was 4.563 g (98%) and 95% purity.

Step (b): Access to the Chromane

151 mg of trimethyl hydroquinone was dissolved, under argon, in 1 ml ofethyl acetate, and the solution was heated at 75° C. 16.24 mg of zincchloride, 4 microliters of water, and 2 microliters of 37% hydrochloricacid were successively added. Alpha-linallol (154 mg) was added to themixture in 30 mn. After 10 hours at 75° C., the alpha-linallol wasconsumed. 10 microlitres of 37% hydrochloric acid was added. Formationof the chromane was monitored on TLC plates. After 2 hours at 75° C.,the mixture was cooled to 25° C., diluted with ether, washed by a normalsolution of sodium hydroxyde, and with water, dried over magnesiumsulphate, filtered and concentrated. The crude chromane, thus obtained,was diluted in 5 ml of triethyl amine, heated to reflux during fivehours and cooled to 25° C. 204 mg of acetic anhydride was then added,and the mixture was kept at 25° C. 2 h under stirring. The mixture wasconcentrated under vacuum and the residue was chromatographed undersilica gel. The desired acetylated chromane was isolated with a 60%yield (198 mg).

Step (c) Access to the Chromene

151 mg of trimethyl hydroquinone was dissolved under argon in 1 ml ofethyl acetate, and the solution was heated at 75° C. 16.24 mg of zincchloride, 4 microliters of water, and 2 microliters of 37% hydrochloricacid were successively added. Alpha-linallol (154 mg) was added to themixture over a period of 30 minutes. After 10 hours at 75° C., themixture was cooled to 25° C., diluted with ether, washed by a normalsolution of sodium hydroxyde, and with water, then dried over magnesiumsulphate, filtered and concentrated. The crude benzoquinone adduct, thusobtained, was diluted in 5 ml of triethyl amine, heated to reflux duringfive hours and cooled to 25° C. 204 mg of acetic anhydride were added,and the mixture was kept at 25° C. for 2 hours under stirring. Themixture was concentrated under vacuum and the residue waschromatographed under silica gel. The desired acetylated chromene wasisolated with a 50% yield (162 mg).

Step (d):

1 mmol of compound produced in step (b) and 1 mmol of dimethyl octanaldimethyl acetal were dissolved under inert atmosphere in 5 ml ofdichloromethane. The catalyst (5% molar equivalents of scandium triflateor iron trichloride or ytterbium triflate) was added. The mixture waskept under stirring during 15 hours at ambient temperature. 3 ml of asaturated aqueous solution of sodium hydrogeno carbonate was added. Theorganic phase was separated, dried over magnesium sulphate, andconcentrated in vacuo. The crude desired product was purified by columnchromatography on silica gel (eluent: pentane/diethyl ether: 9/1 involume).

Step (e):

1 mmol of compound produced in step (c) and 1 mmol of dimethyl octanaldimethyl acetal were dissolved under inert atmosphere in 5 ml ofdichloromethane. The catalyst (5% molar equivalents of scandium triflateor iron trichloride or ytterbium triflate) was added. The mixture waskept under stirring during 15 hours at ambient temperature. 3 ml of asaturated aqueous solution of sodium hydrogeno carbonate was added. Theorganic phase was separated, dried over magnesium sulfate, andconcentrated in vacuo. The crude desired product was purified by columnchromatography on silica gel (eluent: pentane/diethyl ether: 9/1 involume).

Step (f):

1 mmol of the product formed in steps (e) and (d), along with thecatalyst (palladium 5% on charcoal; 5% weight equivalents), were placedin an autoclave. Diethyl ether (5 ml) was added. The autoclave waspurged with argon prior to sealing. Hydrogen was then introduced (1 to 5bars) into the autoclave to initiate the reaction. At the end of thereaction, the pressure was reduced to atmospheric pressure. Theautoclave was then opened. Vitamin E was obtained after usual make-up ofthe mixture.

1. A process for the preparation of a compound of general formula (I)

wherein A is a C₁ to C₂₀ hydrocarbon, Y and Z independently represent aC₁ to C₂₀ hydrocarbon which may contain an oxygenated functional group,B represents OR¹ or NHR¹ where R¹ is hydrogen or a C₁ to C₆ hydrocarbon,said process comprising reacting, in the presence of a Lewis acidcatalyst, a compound of the general formula (II)

wherein Y and Z are as herein before defined, with a compound of thegeneral formula (III) or a compound of general formula (IV)

wherein A is as hereinbefore defined, B′ represents O or NR¹ where R¹ isas hereinbefore defined, and R is hydrogen or a C₁ to C₆ hydrocarbon. 2.A process as claimed in claim 1 in which Y is a C₁ to C₂₀ hydrocarbonwith an oxygen group, Z is methyl, A is an aliphatic hydrocarbon and Ris CH₃.
 3. A process as claimed in claim 1 in which compounds of formula(II) are 6-methyl-6-heptene-2-one; 6-acetoxy 2,5,7,8-tetramethyl2-[(4-methyl pent-4-ene)-1 yl]chromeme or 6-acetoxy 2,5,7,8-tetramethyl2-[(4-methyl pent-4-ene)-1 yl]chromane.
 4. A process as claimed in claim1 in which compounds of formula (III) are 3 methyl butanal; imines of3-methyl butanal; 3,6-dimethyl octanal; imines of 3,6-dimethyl octanal;citral and imines of citral.
 5. A process as claimed in claim 1 in whichcompounds of formula (IV) are acetals of citral; acetals of 3-methylbutanal or acetals of 3,6-dimethyl octanal.
 6. A process as claimed inclaim 1 in which the Lewis acid is of general formula M(L)_(n) where Mrepresents aluminum, iron, magnesium, scandium, ytterium, zinc,titanium, silicium and bismuth; L represents a halide, CF₃SO₃,(CF₃SO₂)₂N, ClO₄ or a C₁ to C₄ alkyl, and n corresponds to theelectronic valency of M, or is of general formula A-H wherein Arepresents CF₃SO₃ or (CF₃SO₂)₂N.
 7. A process as claimed in claim 6 inwhich the Lewis acid is iron trichloride.
 8. A process as claimed inclaim 1 carried out in the presence of a base selected from aromaticamines, aliphatic amines and carbonate salts of Group I or II of thePeriodic Table.
 9. A process as claimed in claim 1 carried out in thepresence of an organic solvent selected from chlorinated solvents,organic solvents, ether solvents, nitrile solvents and nitro solvents.10. A process as claimed in claim 1 carried out at a temperature of from−80 to +150° C. and under atmospheric pressure.
 11. A compound havingthe structure of one of the following structures


12. A process for the preparation of phytone and/or Vitamin E whichcomprises hydrogenolysis of the compound of general formula (I) asdefined in claim
 1. 13. A process as claimed in claim 12 in which thehydrogenolysis is carried out in the presence of a catalyst which is ametal selected from palladium, platinum, nickel and zinc or a metal saltstannium chloride or molybdenum(III).
 14. A process as claimed in claim13 in which the hydrogenolysis is carried out in the presence ofpalladium on charcoal.
 15. A process for the preparation of Vitamin Ewhich comprises the hydrogenolysis of compound (VII) or (VIII) asdefined in claim
 11. 16. A process for the preparation of phytone whichcomprises hydrogenolysis of compound (V) or (VI) as defined in claim 11.17. A process as claimed in claim 1, wherein Y and Z independentlyrepresent a C₁ to C₂₀ hydrocarbon.
 18. A process as claimed in claim 6,wherein n is from 1 to
 4. 19. A process as claimed in claim 1, whereinthe Lewis acid catalyst is present in an amount of from 0.001 to 5 molarequivalents.
 20. A process as claimed in claim 1, wherein the Lewis acidcatalyst is present in an amount of from 0.02 to 2.5 molar equivalents.21. A process as claimed in claim 1, wherein the mole ratio of thecompound of general formula (II) to the compound of general formula(III) or the compound of general formula (IV) is from 0.2:1 to 5:1. 22.A process as claimed in claim 1, wherein the mole ratio of the compoundof general formula (II) to the compound of general formula (III) or thecompound of general formula (IV) is from 0.5:1 to 2:1.
 23. A process asclaimed in claim 1, said process being conducted at a temperaturebetween −80 and 150° C.
 24. A process as claimed in claim 1, saidprocess being conducted at a temperature between −50 and 25° C.
 25. Aprocess as claimed in claim 1, said process being conducted atatmospheric pressure or higher.
 26. A process as claimed in claim 1,wherein the compounds are reacted for 30 minutes to 24 hours.